Strategies to prevent the formation of plaque and to resolve existing plaque are urgently needed to treat atherosclerosis, the primary cause of heart disease and stroke, and the most common cause of morbidity and mortality worldwide. The existing means of intervention provide substantial benefits to patients with atherosclerosis, but side effects and limited access of therapeutic agents to plaque interior remain major obstacles to success of such therapies (Charo and Taub, Nat Rev Drug Discov. 2011; 10(5):365-376).
Specific molecular signatures distinguish the endothelium covering atherosclerotic plaques from normal endothelium. These signatures can be used to target diagnostics and therapeutics to plaque. Drugs coupled to a homing molecule, such as a peptide, become concentrated at the target tissue (synaphic or active targeting), resulting in increased efficacy and/or decreased side effects (reviewed in Ruoslahti et al., J Cell Biol. 2010; 188(6):759-768). One plaque marker is VCAM-1, which can be engaged with antibodies and a peptide ligand (e.g., Nahrendorf et al., JACC Cardiovascular imaging. 2009; 2(10):1213-1222). In vivo phage display has been used in search for additional markers of plaques, and peptides that selectively recognize the endothelium over plaques have been reported (Houston et al., FEBS letters. 2001; 492(1-2):73-77; Liu et al., American J Pathology. 2003; 163(5):1859-1871). The binding molecules (receptors) for these peptides have not been identified.
The clot-binding peptide CREKA (Simberg et al., Proc Natl Acad Sci USA. 2007; 104(3):932-936) has been used to target the subtle clotting that occurs on the surface of atherosclerotic plaques (Peters et al., Proc Natl Acad Sci USA. 2009; 106(24):9815-9819). CREKA also homes to tumors (Simberg et al., Proc Natl Acad Sci USA. 2007; 104(3):932-936). Another tumor-homing peptide, LyP-1, can home to the surface of plaques, penetrate into the plaque interior, and accumulate there (Hamzah et al., Proc Natl Acad Sci USA. 2011; 108(17):7154-7159).
LyP-1 is a cyclic nonapeptide that specifically recognizes lymphatic vessels, macrophages, and tumor cells in certain tumors; it shows no binding to any normal tissues (Fogal et al., Cancer Res. 2008; 68(17):7210-7218; Laakkonen et al., Proc Natl Acad Sci USA. 2004; 101(25):9381-9386; Laakkonen et al., Nat Med. 2002; 8(7):751-755). The primary receptor for the LyP-1 peptide is p32/p33/gC1qR/HABP1 (p32; Fogal et al., Cancer Res. 2008; 68(17):7210-7218). Numerous extracellular and intracellular proteins, and even hyaluronic acid have been reported to bind to p32; indeed, p32 may be a multifunctional chaperone (Bialucha et al., J Cell Biol. 2007; 178(4):575-581; Storz et al., J Biol Chem. 2000; 275(32):24601-24607). Crystallography shows p32 as a doughnut-shaped trimer (Jiang et al., Proc Natl Acad Sci USA. 1999; 96(7):3572-3577). The main location of p32 is in the mitochondria (Matthews and Russell, J General Virology. 1998; 79 (Pt. 7):1677-1685), but other subcellular locations have been reported, including the cell surface (Ghebrehiwet et al., J Experimental Medicine. 1994; 179(6):1809-1821). The mitochondrial and cell surface localization has been confirmed (Fogal et al., Cancer Res. 2008; 68(17):7210-7218; Laakkonen et al., Proc Natl Acad Sci USA. 2004; 101(25):9381-9386; Laakkonen et al., Nat Med. 2002; 8(7):751-755). In yeast (Muta et al., J Biol Chem. 1997; 272(39):24363-24370) and mammalian cells (Fogal et al., Mol Cell Biol. 2010; 30(6):1303-1318), p32 regulates mitochondrial oxidative phosphorylation. A link to autophagy has been proposed (Reef et al., Oncogene. 2007; 26(46):6677-6683). Elevated expression of p32 has been noted in cancer (Fogal et al., Cancer Res. 2008; 68(17):7210-7218) and in atherosclerotic plaques (Hamzah et al., Proc Natl Acad Sci USA. 2011; 108(17):7154-7159; Peerschke et al., Molecular immunology. 2004; 41 (8):759-766).
It is an object of the present invention to provide compositions for treatment of atherosclerosis.
It is a further object of the present invention to provide compositions for prevention, inhibition, or reduction of atherosclerosis.
It is a further object of the present invention to provide compositions for treatment of atherosclerotic plaques.
It is a further object of the present invention to provide compositions for prevention, inhibition, or reduction of atherosclerotic plaques.
It is a further object of the present invention to provide methods for treatment of atherosclerosis.
It is a further object of the present invention to provide methods for prevention, inhibition, or reduction of atherosclerosis.
It is a further object of the present invention to provide methods for treatment of atherosclerotic plaques.
It is a further object of the present invention to provide methods for prevention, inhibition, or reduction of atherosclerotic plaques.